Aldosterone, a steroid hormone synthesized by the adrenal glomerulosa, is normally produced in two conditions, intravascular volume depletion and hyperkalemia (high plasma K+ level) (Spät and Hunyady, 2004, Physiol. Rev. 84:489). Volume depletion activates the renin-angiotensin system, producing the hormone angiotensin II (AII), which signals via its G protein-coupled receptor (GPCR) in glomerulosa cells. The resting membrane potential is set by K+ channel activity (Spät, 2004, Mol. Cell. Endocrinol. 217:23); both AII signaling and hyperkalemia cause membrane depolarization and activation of voltage-gated Ca2+ channels. Increased intracellular Ca2+ provides the normal signal for aldosterone production, and sustained increases lead to glomerulosa cell proliferation (Spät and Hunyady, 2004, Physiol. Rev. 84:489; McEwan et al., 1996, Am. J. Physiol. 271, E192; Pawlikowski et al., 2001, Endocr. Regul. 35:139; Tanabe et al., 1998, J. Endocrinol. Invest. 21:668); All also causes increased inositol 1,4,5-trisphosphate (IP3) and transient Ca2+ release from intracellular stores. Aldosterone signaling in the kidney increases electrogenic Na+ reabsorption, defending intravascular volume, and also increases K+ secretion.
In primary aldosteronism, the adrenal gland constitutively produces aldosterone in the absence of AII or hyperkalemia, resulting in hypertension and variable hypokalemia (low plasma K+ level). Primary aldosteronism is found in ˜10% of patients referred for evaluation of hypertension. A third or more of these have aldosterone-producing adenoma (APA, also known as Conn's syndrome) of the adrenal cortex (Rossi et al., 2006, J. Am. Coll. Cardiol. 48:2293); of the remainder, a small fraction have mutations that cause constitutive expression of aldosterone synthase (Lifton et al., 1992, Nature 355:262), and the rest are classified as idiopathic.
APAs are typically solitary, well circumscribed, and diagnosed between ages 30 and 70 (V. Kumar. A. K. Abbas, N. Fausto, J. C. Aster, Eds., in Robbins and Cotran Pathologic Basis of Disease (Saunders, Philadelphia, ed. 8, 2009), chap. 24). They come to medical attention due to new or worsening hypertension, often with hypokalemia. Aldosterone is elevated while renin levels are suppressed (reflected in a high aldosterone:renin ratio), and a characteristic adrenal mass can be seen on computed tomography (CT). Adrenal vein sampling demonstrates predominant aldosterone secretion from the gland harboring the tumor. APAs virtually always remain benign, without local invasion or distant metastasis (Ghose et al., 1999, Ann. Intern. Med. 131:105). Surgical removal ameliorates or cures hypertension in the large majority of patients (Calvo-Romero and Ramos-Salado, 2000, Postgrad. Med. J. 76:160). The mechanisms responsible for neoplasia and cell-autonomous aldosterone production are unknown.
Screening studies of hypertensive patient populations have revealed primary aldosteronism as the most common cause of secondary hypertension, and together with recognition of the association with severe cardiovascular complications, have produced a renewed focus on the syndrome of primary aldosteronism (Young, 2007, Clin Endocrinol (Oxf) 66:607-618; Gordon et al., 1992, Lancet 340:159-161; Rossi et al., 2006, J Am Coll Cardiol. 48:2293-2300; Rossi et al., 2008, J Hypertens 26:613-621; Rossi, 2011, Endocrinol Metab Clin North Am. 40:313-332; Stowasser and Gordon, 2003, Primary aldosteronism. Best Pract Res Clin Endocrinol Metab. 17:591-605). This has led to marked improvement in guidelines for case detection, diagnosis and treatment (Funder et al., 2008, J Clin Endocrinol Metab. 93:3266-3281). Case detection has been recommended in all patients with hypertension, and should be based on PAC/PRA (or PRC) ratio (with laboratory dependent cut-off values), and confirmation of the diagnosis by either of various suppression tests (oral sodium loading, saline infusion, captopril test, and fludrocortisone suppression tests) (Gordon et al., 1992, Lancet 340:159-161; Rossi, 2011, Endocrinol Metab Clin North Am. 40:313-332; Funder et al., 2008, J Clin Endocrinol Metab. 93:3266-3281; Westerdahl et al., 2009, Scand J Clin Lab Invest. 69:234-241). The combination of adrenal CT and adrenal vein sampling is recommended for identification of unilateral lesions, which are potentially curable by surgery, and for appropriate lateralization diagnosis prior to operation (Funder et al., 2008, J Clin Endocrinol Metab. 93:3266-3281). CT identification of a unilateral adrenal lesion in younger patients (<40 years) with primary aldosteronism may represent an appropriate indication for surgery, although demonstration of lateralization of aldosterone secretion is otherwise claimed to be essential to maximize benefits of surgical intervention (Young, 2007, Clin Endocrinol (Oxf) 66:607-618; Funder et al., 2008, J Clin Endocrinol Metab. 93:3266-3281; Mathur et al., 2010, J Am Coll Surg. 211:384-390).
Despite the advances made in the genetic classification and treatment of adrenal diseases and disorders, there is a need in the art for the further discovery of novel mutations that can drive the development of diagnostics and the selection of targeted therapies to treat adrenal diseases and disorders. The present invention fulfills these needs.